Steiner Donald J, Furuya Yoichi, Jordan Michael B, Metzger Dennis W
Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Infect Immun. 2017 May 23;85(6). doi: 10.1128/IAI.00064-17. Print 2017 Jun.
causes lethal pneumonia following infection of the lungs by targeting macrophages for intracellular replication; however, macrophages stimulated with interferon gamma (IFN-γ) can resist infection We therefore hypothesized that the protective effect of IFN-γ against requires macrophages receptive to stimulation. We found that the lethality of pulmonary LVS infection was exacerbated under conditions of alveolar macrophage depletion and in mice with a macrophage-specific defect in IFN-γ signaling (termed mice with macrophages insensitive to IFN-γ [MIIG mice]). We previously found that treatment with exogenous interleukin 12 (IL-12) protects against infection; this protection was lost in MIIG mice. MIIG mice also exhibited reduced neutrophil recruitment to the lungs following infection. Systemic neutrophil depletion was found to render wild-type mice highly sensitive to respiratory infection, and depletion beginning at 3 days postinfection led to more pronounced sensitivity than depletion beginning prior to infection. Furthermore, IL-12-mediated protection required NADPH oxidase activity. These results indicate that lung macrophages serve a critical protective role in respiratory LVS infection. Macrophages require IFN-γ signaling to mediate protection, which ultimately results in recruitment of neutrophils to further aid in survival from infection.
通过靶向巨噬细胞进行细胞内复制，在肺部感染后引发致命性肺炎；然而，用干扰素γ（IFN-γ）刺激的巨噬细胞可以抵抗感染。因此，我们假设IFN-γ对[病原体名称未明确]的保护作用需要对刺激有反应的巨噬细胞。我们发现，在肺泡巨噬细胞耗竭的情况下以及在IFN-γ信号传导存在巨噬细胞特异性缺陷的小鼠（称为对IFN-γ不敏感的巨噬细胞小鼠[MIIG小鼠]）中，肺部[病原体名称未明确]LVS感染的致死率会加剧。我们之前发现，用外源性白细胞介素12（IL-12）治疗可预防[病原体名称未明确]感染；这种保护作用在MIIG小鼠中丧失。MIIG小鼠在感染后肺部的中性粒细胞募集也减少。发现全身性中性粒细胞耗竭会使野生型小鼠对呼吸道[病原体名称未明确]感染高度敏感，并且在感染后3天开始耗竭比在感染前开始耗竭导致更明显的敏感性。此外，IL-12介导的保护作用需要NADPH氧化酶活性。这些结果表明，肺巨噬细胞在呼吸道[病原体名称未明确]LVS感染中起关键的保护作用。巨噬细胞需要IFN-γ信号传导来介导保护作用，这最终导致中性粒细胞的募集，以进一步帮助从感染中存活。
